The optimal treatment strategy for patients with metastatic hormone-refractory prostate cancer (HRPC) continues to represent a challenge for oncologists. The median survival duration of patients with metastatic HRPC is about 12 months [1-3]. Although chemotherapy with mitoxantrone offers a palliative benefit [1, 2], no treatment has been shown to prolong survival. Recently, phase II trials of estramustine-based or taxane-based regimes reported a≧50% decrease in levels of serum prostate-specific antigen (PSA) in 45% to 67% of patients [4-8]. However, these combinations were associated with a significant degree of nausea, diarrhea, leukopenia, and cumulative fluid retention and an increased risk for thrombotic events, precluding its use in patients with a poor performance status. In addition, none of these regimes is associated with prolonged survival and the number of patients in these studies was limited.
Many tumor antigens recognized by human leukocyte-associated antigens (HLA) class I-restricted cytotoxic T lymphocytes (CTLs) have been identified in the past decade [9, 10], and new approaches for HRPC with tumor vaccines have been investigated. Phase I/II clinical trials with dendritic cell-based immunotherapy have been conducted, and also a vaccine comprising a recombinant prostate-specific membrane antigen (PSMA) and an adjuvant has been tested in prostate cancer patients [11, 12]. Our approach in the immunotherapy for HRPC patients is a pre-vaccination measurement of peptide-specific CTL precursors in the circulation of cancer patients reactive to 30 kinds of vaccine candidates with the ability to induce CTLs, followed by administration of only reactive peptides (patient-oriented peptide vaccination) as reported previously [13, 14]. We recently completed our phase I clinical trial for HRPC to assess the safe administration of these peptides [15]. The adverse events of this immunotherapy were less severe than those of conventional therapies although the clinical responses of this trial have been limited. It is suggested that additive anti-tumor effects could be achieved by combination of peptide vaccination and cytotoxic agents when the cytotoxic agents had minimum suppression of immune system.
Estramustine phosphate is a stable conjugate of estradiol and nitrogen mustard that possesses anti-mitotic properties and causes disruption of microtubule organization [16]. Estramustine phosphate has been subjected to many Phase II and III clinical trials in the last 25 years as a second-line treatment of HRPC in addition to primary treatment. The advantage of estramustine phosphate over other cytotoxic drugs is its ease of administration (oral) and relatively good tolerability at the effective dose.
Combination of immunotherapy and cytotoxic drugs is not a new concept [27], but there have been major concerns about a negative interaction which might take place due to the myelosuppressive properties of many cytotoxic drugs. Cytotoxic drugs also preferentially kill cells in division, a hallmark of an activated immune system, and therefore could inhibit immune responses. However, myelosuppression has rarely been reported as a toxicity of estramustine phosphate in patients treated for HRPC [16]. In a phase III study of estramustine phosphate combined with vinblastine versus vinblastine alone, the rate of neutropenia was lower in the combination arm versus the monotherapy arm (grades 2, 3, 4: 7%, 1% and 1% versus 27%, 18% and 9%, respectively)[3].